Labeled biomolecules are essential to a wide array of methods used for biological research, medical diagnosis and therapy. Labeled biomolecules permit a researcher or clinician to detect the location, size, amount or other properties of biomolecules of interest. Commonly labeled biomolecules include, among others, nucleotides, oligonucleotides, nucleic acids, amino acids, peptides and polypeptides, proteins, carbohydrates and lipids.
Nucleic acid hybridization is one of the most frequently used methods requiring labeled nucleic acid probes, and is used in both research and diagnostic medicine. Methods utilizing nucleic acid hybridization include, for example, fluorescent in-situ hybridization (FISH), DNA in-situ hybridization (DISH; Singer and Ward, 1982, Proc. Natl. Acad. Sci. U.S.A. 79: 7331-7335), RNA in-situ hybridization (RISH; Singer et al., 1986, BioTechniques 4: 230-250), multi-color fluorescent in-situ hybridization (MFISH), gene mapping (Pitta et al., 1990, Strategies 3: 33), Southern and Northern blots (Southern, 1975, J. Mol. Biol. 98: 503-517; Alwine et al., 1977, Proc. Natl. Acad. Sci. U.S.A. 74: 5350-5354), microarray-based assays (Callow et al., 2000, Genome Res. 10: 2027-2029) and diagnostic array assays, among others. Radioisotopes are perhaps the most commonly used detectable labels for nucleic acid hybridization. However, there is a need in the art for non-isotopic alternatives to radiolabeling because isotopic labels are expensive, dangerous to handle and have increasingly expensive disposal costs.
An ideal non-radioactive labeled probe for nucleic acid hybridization should have the following properties: 1) label that is easily attached to the probe; 2) stability under various separation/purification conditions such as gel electrophoresis, HPLC, TLC or column purification; 3) stability under nucleic acid hybridization conditions, such as exposure to solutions containing detergents and formamide, and temperatures up to 100xc2x0 C.; 4) label that does not interfere with hybridization to a complementary target; 5) label that is detectable at very low amounts, ideally 1 attomole of nucleic acid or less; 6) applicability to solution or solid-phase hybridization assays such as those performed on membranes, microtiter plates and microarrays (gene chips); 7) adaptability to homogeneous assay formats wherein the hybridized probe is detectable and distinguishable from unhybridized probe in solution; 8) long shelf-life for storage; and 9) compatibility with automated analysis and high throughput instruments.
Enzymatic Labeling Methods
Labels are generally attached to nucleic acids using either enzymatic or chemical means. Enzymatic methods are useful for both end-labeling of existing strands of nucleic acid and for the template-dependent internal labeling of nucleic acid strands polymerized in vitro or in vivo. There are several different approaches taken to the enzymatic generation of end-labeled nucleic acid probes. Polynucleotide kinase is often used to label the 5xe2x80x2 end of a polynucleotide strand with a radioactive phosphate (e.g., 32P or 33P) transferred from the gamma position of labeled ATP. Kinase labeling results in, at best, a single radioactive phosphate label moiety per polynucleotide strand. Alternatively, end-labeled probes comprising more than one label moiety per strand can be generated by a 3xe2x80x2-tailing reaction catalyzed by terminal transferase (Roychoudhury et al., 1980, Nucleic Acids Res. 6: 1323-1333). However, the optimal reaction conditions vary for the incorporation of the various nucleotides by terminal transferase, and conditions vary for each different probe to be labeled. Another alternative for end-labeling probes is to use PCR to make 5xe2x80x2 end-labeled DNA probes through incorporation of a 5xe2x80x2-labeled primer. This approach can rapidly generate a significant quantity of extended, end-labeled probes. However, the PCR method requires first generating the end-labeled primer at high specific activity.
There are also a number of approaches for generating internally labeled probes using enzymes. One of the commonly used enzymatic techniques is xe2x80x9cRandom-Primedxe2x80x9d labeling, (Feinberg and Vogelstein, 1983, Anal. Biochem. 132: 6-13; Feinberg and Vogelstein, 1984, Anal. Biochem. 137: 266-267). The resulting labeled probe is a mixture of different sized sequences of the template. The ratio between primer and template, and the amount of labeled and unlabeled nucleotide are varied to obtain the highest specific activity probes. An alternative internal labeling method is xe2x80x9cNick Translationxe2x80x9d (Rigby et al., 1977, J. Mol. Biol. 133: 237-251). In this procedure, a mixture of the endonuclease Dnase I and 5xe2x80x2xe2x86x923xe2x80x2 DNA polymerase Pol I is used, and the ratio of these two enzymes and the percentage of labeled nucleotide determines the amount and length of the labeled DNA. Another alternative for generating an internally-labeled probe is the Polymerase Chain Reaction (PCR; Mullis et al., 1986, Cold Spring Harb. Symp. Quant. Biol. 51 Pt. 1: 263-273), performed in the presence of a mixture of labeled and unlabeled nucleotides. For mRNA analysis, reverse transcription (RT) in the presence of labeled deoxyribonucleotides is the traditional method to create labeled cDNA (Varmus and Swanstrom, 1979, in Molecular Biology of Tumor Viruses, vol.2: RNA Tumor Viruses (Weiss et al., Eds) pp. 369-512, Cold Spring Harbor Press, Cold Spring Harbor, N.Y.).
In any enzymatic labeling method, the reaction conditions and the ratio of labeled to unlabeled nucleotides should be optimized for every labeling reaction, thereby complicating the labeling procedure. Each of the enzymatic labeling methods described above, and other enzymatic methods known to those skilled in the art, tend to work well for the incorporation or attachment of radiolabeled species. In general, isotopic labels do not interfere with the function of the enzymes to label nucleic acids. In contrast, labeling moieties other than isotopes tend to be large and can interfere with the labeling reactions, such that relatively poor incorporation rates and low total incorporation of the label is observed. The relatively poor recognition and incorporation of nucleotides labeled with non-isotopic moieties, such as fluorescent molecules, can sometimes be compensated by increasing the absolute concentration and modifying the ratio of the labeled nucleotide in the reaction. However, even when this approach works, the cost of the labeling reaction is increased. In addition, variation in enzyme quality, resulting for example from storage or frequent freeze/thaw cycles, can result in variable labeling reaction efficiency.
A common alternative solution to the problem of poor incorporation of nucleotides labeled with larger non-isotopic markers is to enzymatically incorporate a nucleotide modified with a small affinity moiety, such as biotin or digoxigenin, into a probe sequence. The probe may then either be directly reacted with a labeled affinity binding partner, such as avidin or anti-digoxigenin antibodies, or it may be hybridized to target nucleic acid and then reacted with a labeled affinity binding partner. The biotin/avidin system is characterized by subpicogram sensitivity (Feinberg and Vogelstein, 1983, supra; Feinberg and Vogelstein, 1984, supra). A disadvantage of this method is its high non-specific background due to the inherent positive charge exhibited by avidin at neutral pH and the endogenous ubiquity of vitamin H (biotin) in biological samples. This method also suffers from problems discussed above related to variations in enzyme activity leading to variable labeling reaction efficiency.
Chemical Labeling Methods
Chemical labeling methods are an alternative to the enzymatic labeling methods. Among methods for direct derivatization of nucleic acids with detectable markers are photolabeling reactions using aryl azide compounds (Forster et al., 1985, Nucleic Acids Res. 13: 745-761) psoralen, angelicin, acridine dyes (Chimino et al., 1985, Ann. Rev. Biochem. 54: 1151-1193), or direct intercalation with detectable dyes such as ethidium bromide or fluoren derivatives (Al-Hakeem and Hull, 1986, Nucleic Acids Res. 14: 9965-9976). These methods are limited by low labeling efficiency and some of the labeling compounds are toxic.
Alternative chemical labeling methods are available in which detectable haptens are introduced into the DNA probe via an activated linker arm. Primary modification of the nucleic acids is obtained either by transamination(Viscid et al., 1986, J. Clin. Microbiol. 23: 311-317), mercuration (Dale et al., 1975, Biochemistry 14: 2447-2457), bromination, thiolation, or amine substitution with bifunctional reagents, followed by coupling with activated linker arms carrying a detectable hapten. For example, allylamine moieties can be introduced into DNA probes by mercuration/substitution (Id.) or by enzymatic incorporation of an allylamine modified nucleotide. The allylamine tethered probe can then react with the N-hydroxysuccinimide (NHS) ester of biotin or a fluorescent dye (Langer et al., 1981, Proc. Natl. Acad. Sci. U.S.A. 78: 6633-6637; Hopman et al., 1986, Nucleic Acids Res. 14: 6471-6488). For the enzymatic incorporation of allylamine-modified nucleotides, one needs to optimize the ratio of the allylamine dNTP and unmodified dNTP. In addition, the coupling yield of an allylamine tagged probe with dye-NHS ester may be reduced due to the instability of dye-NHS ester in water (Molecular Probes, 1997, Product Information, Amine-Reactive Probes). The half-life of dye-NHS ester in aqueous solution at neutral pH is approximately 10-20 minutes, and is even shorter under conditions generally used for the coupling reaction (e.g., pH 8.5-9.1). As an alternative, chemical labeling of oligonucleotides can also be performed internally or at both termini during automated oligonucleotide synthesis by incorporation of protected allylamine synthetic components which are then reacted with NHS esters of haptens of interest (Haralambidis et al., 1987, Nucleic Acids Res. 15: 4857-4867). The degree of labeling is limited due to the short length of synthetic oligonucleotides.
The complexity of the DNA labeling methods described above not only related to enzyme and dye-NHS ester instability, but also because multiple steps are required to optimize the labeling reaction conditions. There is a need to develop a simple reliable method to make labeled DNA probes with high efficiency.
Chemical Labeling Methods Using Platinum Compounds
Platinum (atomic number 78, atomic weight 195) is a transition metal with an outer electronic configuration of 4f145d96s1. As a d-block metal, Pt(II) tends to gain an additional four electrons to form a square-planar four coordination Pt(II) complex (FIG. 1; Cotton et al. in Advanced Inorganic Chemistry (6th ed), John Wiley and Sons, Inc., NY, pp. 1063, 1072, 1076). In this complex, the Pt(II) ion acts as an electron acceptor (Lewis acid), showing a high affinity for xe2x80x9csoftxe2x80x9d ligands such as heavier halogens, phosphines, sulfides, nitrogen compounds, alkenes, alkynes, and other xcfx80-bond compounds.
FIG. 1 also shows the structures of cis- and trans-diaminedichloro-platinum(II) (DDP). In these complexes, two relatively inert ligands, such as amine, sulfur or nitrogen containing compounds, or other electron donating groups linked to a reporter, act as stabilizers while the other two groups are labile (e.g., chloride ions). Platinum complexes such as these have a marked affinity for the N7-nitrogen atom in the purine nucleotide bases guanine and adenine in nucleic acids (FIG. 2). Upon reaction with nucleic acids, the labile chlorine atoms are displaced and Pt carrying the marker group, forms a non-covalent but irreversible adduct with the nucleotide bases, particularly guanine and adenine. The resulting adduct does not interfere with hybridization of DNA to its complementary target. Studies have shown that cis-DDP mainly forms intrastrand cross links to adjacent bases GG (47-50%) and AG (23-28%), and that less than 10% of cis-DDP formed intrastrand cross-links with adjacent guanines on the opposite strand of double stranded DNA (Fichtinger-Schlepman et al., 1985, Biochemistry 24: 707). cis-Platinum complexes with a single leaving group can also link to nucleic acid bases at individual G and A residues to form adducts (FIG. 3). Because platinum complexes are water soluble and chemically stable, no precipitation occurs at neutral pH, as can happen with other transition metal complexes.
cis-Platinum labeling compounds are disclosed in U.S. Pat. Nos. 5,985,566, 5,580,990, 5,714,327, 4,843,161, 4,569,932 and 4,207,416, International Patent Applications WO 92/01699, WO 96/35696, WO98/15564 and EP 0539466B1. A number of other cis-platinum compounds are known in the art for their activity as inhibitors of DNA synthesis, making them useful as chemotherapeutic agents.
The novel cis-platinum labeling compounds disclosed herein are useful for the direct, rapid, simple and highly efficient labeling of nucleic acids for hybridization assays, including single- or double-stranded DNA, RNA, PNA, oligonucleotides, and homoduplexes, heteroduplexes and multiplexes thereof. The novel compounds disclosed herein are also useful for the rapid, high efficiency labeling of any biomolecule of interest that has an available nitrogen or sulfur group, including, for example, nucleotides and nucleosides, amino acids, peptides, polypeptides, proteins, enzymes, glycoproteins, lipoproteins and other peptide based biomolecules, whether naturally occurring or synthetic, carbohydrates and lipids.
The invention provides novel platinum-based labeling compounds which, upon reaction with biomolecules serve to irreversibly attach detectable markers to those biomolecules. The platinum-based labeling compounds attach to the target biomolecules via coordination of the platinum (II) metal center with nitrogen or sulfur atoms on the target biomolecule.
The invention further encompasses a method for making platinum-based labeling compounds.
The invention further encompasses nucleic acid probe molecules labeled with the disclosed novel platinum-based labeling compounds and methods for making such labeled probe molecules.
The invention further encompasses methods of using probes labeled with platinum-based labeling compounds according to the invention. While any method calling for a labeled probe can make use of probes labeled with platinum-based labeling compounds according to the invention, preferred methods include array and microarray hybridization assays.
Further, the invention encompasses kits for labeling biomolecules using the novel platinum-based labeling compounds disclosed herein.
The invention encompasses a composition comprising the formula: 
wherein:
R1-R5 may be the same or different and are independently selected from the group consisting of H, alkyl (1 to 10 carbon atoms), benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R6, xe2x80x94(Cxe2x95x90O)OR6, or xe2x80x94OCH2(Cxe2x95x90O)R6 and a salt, wherein R6 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X1 and X2 may be the same or different and X is a leaving group; and
linker is a moiety joining a nitrogen to a detectable marker, D.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen CN, OCOR7, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-demethyl-phenyl-4-sulfate, wherein R7 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R6, xe2x80x94(Cxe2x95x90O)OR6, xe2x80x94OCH2(Cxe2x95x90O)R6 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula: 
wherein:
R1-R5 may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R6, xe2x80x94(Cxe2x95x90O)OR6, or xe2x80x94OCH2(Cxe2x95x90O)R6 and a salt, wherein R6 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X1 and X2 may be the same or different and X is a leaving group; and
linker is a moiety joining a nitrogen to a detectable marker, D.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR7, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R7 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R6, xe2x80x94(Cxe2x95x90O)OR6, xe2x80x94OCH2(Cxe2x95x90O)R6 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula: 
wherein
Y is selected from the group consisting of O, S, and C;
R1 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R2, xe2x80x94(Cxe2x95x90O)OR2, xe2x80x94OCH2(Cxe2x95x90O)R2, and a salt, wherein R2 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X1 and X2 are the same or different and X is a leaving group;
linker is a moiety joining a nitrogen to a detectable marker, D, and u and v are the same or different and are an integer from 1 to 10.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR3, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R3 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R2, xe2x80x94(Cxe2x95x90O)OR2, or xe2x80x94OCH2(Cxe2x95x90O)R2 and a salt. In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula: 
wherein:
xe2x80x94Y is selected from the group consisting of O, S, and C;
R1-R3 may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R4, xe2x80x94(Cxe2x95x90O)OR4, or xe2x80x94OCH2(Cxe2x95x90O)R4 and a salt, wherein R4 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X1 and X2 are the same or different and X is a leaving group; and
linker is a moiety joining a nitrogen to a detectable marker, D.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR5, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R5 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R4, xe2x80x94(Cxe2x95x90O)OR4, xe2x80x94OCH2(Cxe2x95x90O)R4 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula: 
wherein:
Y is selected from the group consisting of O, S, and C;
R1-R3 may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R4, xe2x80x94(Cxe2x95x90O)OR4, or xe2x80x94OCH2(Cxe2x95x90O)R4 and a salt, wherein R4 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X1 and X2 are the same or different and X is a leaving group; and
linker is a moiety joining a nitrogen to a detectable marker, D.
In one embodiment, the leaving group is selected from the group consisting of No3 halogen, CN, OCOR5, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R5 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R4, xe2x80x94(Cxe2x95x90O)OR4, xe2x80x94OCH2(Cxe2x95x90O)R4 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula 
wherein
Z is selected from the group consisting of (CH2)n, and (CH2)nO(CH2)m, wherein m and n are integers from 2 to 8, inclusive;
R1 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R2, xe2x80x94(Cxe2x95x90O)OR2, or xe2x80x94OCH2(Cxe2x95x90O)R2 and a salt, wherein R2 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X1 and X2 are the same or different and X is a leaving group; and
linker is a moiety joining a nitrogen to a detectable marker, D.
In one embodiment, the leaving group is selected from the group consisting of No3, halogen, CN, OCOR3, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R3 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R2, xe2x80x94(Cxe2x95x90O)OR2, xe2x80x94OCH2(Cxe2x95x90O)R2 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula 
wherein
Z is selected from the group consisting of (CH2)n, and (CH2)nO(CH2)m, wherein m and n are integers from 2 to 8, inclusive;
R1 and R2 may be the same or different and are selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R3, xe2x80x94(Cxe2x95x90O)OR3, or xe2x80x94OCH2(Cxe2x95x90O)R3 and a salt, wherein R3 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X1 is a leaving group; and
linker is a moiety joining a detectable marker, D to the platinum ion.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR4, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R4 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R3, xe2x80x94(Cxe2x95x90O)OR3, xe2x80x94OCH2(Cxe2x95x90O)R3 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula: 
wherein:
R1-R6 may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R7, xe2x80x94(Cxe2x95x90O)OR7, or xe2x80x94OCH2(Cxe2x95x90O)R7 and a salt, wherein R7 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X is a leaving group; and
linker is a moiety joining a detectable marker, D to the platinum ion.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR8, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R8 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R7, xe2x80x94(Cxe2x95x90O)OR6, xe2x80x94OCH2(Cxe2x95x90O)R7 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula 
wherein
R1-R6 may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R7, xe2x80x94(Cxe2x95x90O)OR7, or xe2x80x94OCH2(Cxe2x95x90O)R7 and a salt, wherein R7 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X is a leaving group; and
linker is a moiety joining a detectable marker, D, to the platinum ion.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR8, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R8 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R7, xe2x80x94(Cxe2x95x90O)OR6, xe2x80x94OCH2(Cxe2x95x90O)R7 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a composition comprising the formula: 
wherein
Y is selected from the group consisting of O, S, and C;
R1-R4 may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R5, xe2x80x94(Cxe2x95x90O)OR5, or xe2x80x94OCH2(Cxe2x95x90O)R5 and a salt, wherein R5 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X is a leaving group; and
linker is a moiety joining a detectable marker, D, to the platinum ion.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR6, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R6 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R5, xe2x80x94(Cxe2x95x90O)OR5, xe2x80x94OCH2(Cxe2x95x90O)R5 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker. 
The invention further encompasses a composition comprising the formula:
wherein
Y is selected from the group consisting of O, S, and C;
R1-R4 may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R5, xe2x80x94(Cxe2x95x90O)OR5, or xe2x80x94OCH2(Cxe2x95x90O)R5 and a salt, wherein R5 is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;
X is a leaving group; and
linker is a moiety joining a detectable marker, D, to the platinum ion.
In one embodiment, the leaving group is selected from the group consisting of NO3, halogen, CN, OCOR6, OCO-Phenyl, OCOCH2OC(Phenyl)3, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R6 is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO2, CF3, halogen, Oxe2x80x94R5, xe2x80x94(Cxe2x95x90O)OR5, xe2x80x94OCH2(Cxe2x95x90O)R5 and a salt.
In another embodiment, the linker is selected from the group consisting of: (CH2)n, (CH2)n(CHxe2x95x90CH)mO(CHxe2x95x90CH)p(CH2)q, CO(CH2)n(CHxe2x95x90CH)m(CH2)p, COAr(CH2)n(CHxe2x95x90CH)m(CH2)p, NH2(CH2)nQ, NH2((CH2)nO)m(CH2)tQ, NH2(CH2)mAr(CH2)nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, xe2x80x94Sxe2x80x94Sxe2x80x94, NHCSNH, NHCSO, wherein 
and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.
In another embodiment, the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.
The invention further encompasses a nucleic acid comprising a composition according to the formula above and the additional embodiments described above. In a preferred embodiment, the composition forms an adduct with the nucleic acid.
The invention further encompasses a probe comprising a nucleic acid comprising a composition according to the embodiments described above.
The invention further encompasses a method of labeling a nucleic acid, the method comprising the step of contacting a composition as described above with the nucleic acid.
The invention further encompasses a method of probing a nucleic acid array, the method comprising the steps of contacting the array with a probe as described and detecting signal from the detectable marker.
The invention further encompasses a method of making a platinum labeling compound that comprises a stabilizing bridge, the method comprising the step of contacting potassium tetrachloroplatinate (II) with an aliphatic diamine labeled with a detectable marker, wherein the contacting results in a cis-platinum dichloride labeling compound.
In one embodiment, the aliphatic diamine is a cycloaliphatic diamine.
In another embodiment, the cycloaliphatic diamine is a 1,2-cycloaliphatic diamine.
In another embodiment, the cycloaliphatic diamine is a cyclohexyl diamine.
In another embodiment, the cyclohexyl diamine is a 1,2-cyclohexyl diamine.
In another embodiment, the contacting is performed in aqueous solution at a pH of about 1.5 to 5.5 and at a temperature of about 65xc2x0 C.
Definitions:
As used herein, the term xe2x80x9cplatinum labeling complexxe2x80x9d or xe2x80x9cplatinum labeling compoundxe2x80x9d refers to a molecule that comprises a tetravalent platinum atom, a cycloaliphatic diamine stabilizing bridge, and a detectable marker, wherein the platinum atom has the ability to form an adduct with one or more biomolecules.
As used herein, the term xe2x80x9cbiomoleculexe2x80x9d refers to a molecule found within or made by an organism in nature. The term biomolecule also refers to chemically modified or synthetic forms of molecules found within or made by an organism in nature. Biomolecules of interest include, but are not limited to, nucleic acids (oligonucleotides or polynucleotides of DNA, RNA or PNA), peptides, polypeptides, proteins, carbohydrates and lipids.
As used herein, the term xe2x80x9ccycloaliphatic diaminexe2x80x9d refers to substituted or unsubstituted aliphatic diamines comprising at least one cyclic structure.
As used herein, the term xe2x80x9cadductxe2x80x9d refers to the complex formed by the co-ordination of the platinum atom in a platinum labeling complex to an atom of a biomolecule. In an adduct as used herein, the platinum atom directly participates in the binding of the platinum labeling complex to the biomolecule. The adducts formed by platinum labeling complexes are essentially irreversible.
As used herein, the term xe2x80x9cdetectable markerxe2x80x9d refers to a moiety that, when attached to a biomolecule, confers detectability upon that biomolecule or another molecule to which the biomolecule binds. Fluorescent moieties are preferred detectable markers according to the invention, but detectable markers also include, for example, isotopes, fluorescent proteins and peptides, enzymes, components of a specific binding pair, chromophores, affinity tags as defined herein, antibodies, colloidal metals (i.e. gold) and quantum dots. Detectable markers may be either directly or indirectly detectable. Directly detectable markers do not require additional reagents or substrates in order to generate detectable signal. Examples include isotopes and fluorophores. Indirectly detectable markers require the presence or action of one or more co-factors or substrates. Examples include enzymes such as xcex2-galactosidase which is detectable by generation of colored reaction products upon cleavage of substrates such as the chromogen X-gal (5-bromo-4-chloro-3-indoyl-xcex2-D-galactopyranoside), horseradish peroxidase which is detectable by generation of a colored reaction product in the presence of the substrate diaminobenzidine and alkaline phosphatase which is detectable by generation of colored reaction product in the presence of nitroblue tetrazolium and 5-bromo-4-chloro-3-indolyl phosphate, and affinity tags.
As used herein, the term xe2x80x9cleaving groupxe2x80x9d refers to a moiety that can be displaced from the platinum atom in a platinum labeling complex as described herein, in favor of a molecule to be labeled under appropriate conditions. The selection of leaving groups is within the ability of one skilled in the art, through comparison of the electronegativities of the target molecule and the candidate leaving group. That is, a relatively more electronegative group on the target molecule will tend to displace a relatively less electronegative leaving group. For example, suitable leaving groups for labeling a nucleic acid would include groups that would permit a bond between the platinum ion and the nucleic acid to be formed under appropriate conditions. Leaving groups include, for example, F, NO2, Ots, SOPO4, Cl, Br, I, CN, N3, NR3, OAr, OR, SR, SO2R and NH2, where R is an organic residual group and Ar is an aryl organic residual group. Others include, for example, sulfate, nitrate, phosphate, carbonate and lower alkyl derivatives thereof (e.g., ethylnitrate, propylnitrate, etc.).
As used herein, xe2x80x9cappropriate conditionsxe2x80x9d refers to solutions containing molecules having xe2x80x9csoftxe2x80x9d ligands such as heavier halogens, phosphines, sulfides, nitrogen compounds such as amines, adenine, adenosine and its derivatives, guanine, guanosine and its derivatives, DNA, RNA, PNA, alkenes, alkynes and other xcfx80-compounds, heated to 15-100xc2x0 C. between 0.5 to 120 minutes.
As used herein, the term xe2x80x9cfluorophorexe2x80x9d refers to a detectable moiety that, upon absorbing light energy of a given wavelength (the xe2x80x9cexcitation wavelengthxe2x80x9d), is excited and emits light of a longer wavelength (the emission wavelength).
As used herein, the term xe2x80x9cchromophorexe2x80x9d refers to a chemical group capable of selective light absorption resulting in the coloration of compounds or entities containing it.
As used herein, the term xe2x80x9caffinity tagxe2x80x9d refers to a moiety that is selectively bound by an affinity reagent. The attachment of an affinity tag to a biomolecule confers upon the biomolecule the ability to be selectively bound by the affinity reagent. As used herein, the term xe2x80x9caffinity reagentxe2x80x9d refers to an agent that selectively binds to an affinity tag. Useful affinity tag pairs include, for example, antibody and antigen, and biotin and avidin or streptavidin. A pair of molecules exhibits xe2x80x9cselective bindingxe2x80x9d if they physically bind one another in the presence of other different molecules to the substantial exclusion of such different molecules. As used herein, the term xe2x80x9cpolynucleotidexe2x80x9d refers to a polymer of two or more nucleotide monomers or analogs thereof, and includes double- or single-stranded DNA, RNA or PNA (peptide nucleic acid). A xe2x80x9cpolynucleotidexe2x80x9d may comprise modified nucleotides, the modification lying in the backbone sugar moiety, the linkage between nucleotides or in the nucleoside base. For example, the sugar moiety can be a ribose, deoxyribose, dideoxyribose, or a modified form of any of these. The phosphate linkage between nucleotides can be modified as, for example, a phosphorothioate-, methylphosphonate- or phosphoramidate linkage, or the nucleobases can be linked by pseudopeptide linkages in place of sugar-phosphate diester linkages, as in PNAs. The nucleoside base can be, for example, a purine, deazapurine or pyrimidine, for example adenine, guanine, cytosine, thymine, uracil, inosine, deaazaadenine, deazaguanosine, and the like. Non-limiting examples of nucleobase analogs that may be incorporated into a xe2x80x9cpolynucleotidexe2x80x9d as the term is used herein include hypoxanthine, pseudouridine, isocytosine, isoguanine, and 2-thiopyrimidine.
As used herein, the term xe2x80x9coligonucleotidexe2x80x9d refers to a polynucleotide that is between two and about 200 nucleotides in length. An oligonucleotide can be a synthetic (i.e., chemically synthesized) molecule, an enzymatically synthesized molecule or a naturally occurring molecule.
As used herein, the term xe2x80x9cprobexe2x80x9d refers to a biomolecule that specifically binds a target biomolecule or class of target biomolecules. Biomolecules useful as probes are preferably oligonucleotides or polynucleotides, but may include, for example, peptides (including peptide antigens), polypeptides (including, but not limited to antibodies, antigen-binding fragments thereof, and polypeptide antigens), carbohydrates, lipids, hormones and neurotransmitters. As used herein, a xe2x80x9cprobexe2x80x9d is either directly or indirectly detectable.
As used herein, a xe2x80x9cnucleic acid probexe2x80x9d is a polynucleotide of at least 10 nucleotides (nt), 15 nt, 20 nt, 30 nt, 40 nt, 50 nt, 75 nt, 100 nt, 200 nt, 500 nt, 1000 nt, and even up to 5000 to 10,000 nt in length.
As used herein, the term xe2x80x9carrayxe2x80x9d refers to a plurality of biomolecule samples immobilized in distinct locations on a substrate. A nucleic acid array is an array of nucleic acid samples, each sample comprising DNA, RNA, PNA or a polypeptide or protein mixture thereof. A polypeptide or protein array is an array of peptide samples, each sample comprising peptides, oligopeptides, polypeptides, proteins or a mixture thereof
As used herein, the term xe2x80x9clinkerxe2x80x9d refers to a chemical moiety that joins a detectable marker, as defined herein, to a platinum labeling complex according to the invention. The linker can be attached either to a terminal nitrogen of the cycloaliphatic diamine bridge, or it can be coordinated to one of the two platinum coordination sites that does not participate in the bridge structure.